Ideally, the layout of a manufacturing facility should promote efficient flow of work and people. Additionally, the layout should facilitate production, production control, and quality control. For example, the layout should be configured to facilitate quality assurance to minimize defects and operation difficulties, thus ensuring manufacturing and product quality. Quality initiatives also should be built into the facility. This is essential and particularly important for the pharmaceutical manufacturing industry which operates under a strict regulatory environment.
In the United States, the pharmaceutical manufacturing industry must comply with “Current Good Manufacturing Practices” (CGMP) promulgated by the Food and Drug Administration (FDA). See 21 CFR §§210-226. Other regulations or guidelines which the pharmaceutical industry may be subjected to include, for example, World Health Organization GMP guidelines and Pharmaceutical Inspection Co-operation Scheme (PIC/S).
CGMP defines requirements with which a drug manufacturing facility and process must comply. This includes for example, having the building and facility suitably designed and constructed to facilitate cleaning, maintenance and proper operations. See 21 CFR §211.42. The flow of components, drug containers, closures, labeling, in-process materials, and drug products through the building or buildings shall be designed to prevent contamination and defined areas should be configured to prevent mix-ups and contaminations. See 21 CFR §211.42(a)(b)(c). Premises should be laid out in such a way as to allow the production to take place in areas connected in a logical order corresponding to the sequence of the operations and to the requisite cleanliness levels. See PICS 3.7. Also, equipment should be suitably located to facilitate operations for each intended use as well as cleaning and maintenance. See 21 CFR §211.63. Quality Personnel should have access to production area for sampling and investigational as appropriate. See PICS 6.4. There is a need to identify significant steps of operations of equipments, personals and batches. See 21 CFR 211.188-11 & 211.105. These are just some of the myriad of requirements under CGMP.
Non-conformity with CGMP renders a drug “adulterated” under the Food, Drug and Cosmetics Act. See 21 USC §501(a)(2)(B). A drug is deemed adulterated “if the methods used in, or the facilities or the controls used for its manufacture, process, packing or holding do not conform to or are not operated or administered in conformity with CGMP.” The purpose of 21 USC §501(a)(2)(B) is to protect public interest, by ensuring that the drugs marketed meet its regulated claims specifications. To prevent a drug product from being deemed adulterated, a total quality control, approach and system is necessary. A failure to comply with any regulations may result in the drug being withdrawn from the market, as well as subjecting the manufacturer to sanction. This places a heavy burden on the manufacturer to ensure compliance with CGMP.
However, ambiguity in the language of the statute subjects it to interpretation and imparts uncertainty about the requirements for compliance. For example, compliance is not ensured even though the quality manufacturing process or engineering facility is considered “average” compared to the industry. This is because compliance with the regulations requires that a pharmaceutical product must be manufactured by current good manufacturing practice methods, controls and system in order to protect the public. The absence of a consistent and widely accepted interpretation of some of regulatory requirements has led to increased cost in engineering new facilities. This has also led to longer lead-times in engineering and, in some cases, delays in bringing new pharmaceutical products to market. In an attempt to clarify the regulatory requirements, the International Society for Pharmaceutical Engineering and the FDA have cooperated to publish a Baseline® Pharmaceutical Engineering Guide (Guide).
The Guide includes suggestions from the FDA for compliance with CGMP. The main basic philosophy promoted by the Guide is “Good Engineering Practice” (GEP), which is defined as “established engineering methods and standards that are applied throughout the project life cycle to deliver appropriate and cost effective solutions”. It takes into account the design and installation of facilities and equipment and takes “full account of CGMP, safety, health, environmental, ergonomic, operational, maintenance, recognized industry guidance, and statutory requirements”. See Guide. In addition to protecting the integrity of the drugs, the safety of the operators and visitors must be considered in the engineering design.
In an engineering design of a facility, people, material, production system and utility systems are the variable elements that we have to consider and to establish control in order to establish and practice CGMP. For people and material flows, the layout design of the facility is the primary control to establish CGMP. A production layout should also consider the entire life cycle of the product in terms of daily provision for cleaning, utility support area, calibration, monitoring, storage of materials and equipments, and the long term life cycle requirements for qualification, validation, periodical maintenance, changes like retrofitting, renovating, decommissioning, selling, re-starting and even relocating. Therefore, without an effective and efficient layout design, it will be difficult for the management and the operator to practice CGMP efficiently. The controls of the production systems and utility systems, on the other hand, are primarily established by system design and are maintained by monitoring the systems. Therefore, layout and design of the facility are critical controls to establish and practice CGMP. The design goals and issues are to prevent cross contamination, ability to process multiple components concurrently and to ensure integrity of final product. Specifically, layout should allow appropriate access, grouped activities together to maximize flexibility and designated or segregation areas for materials and people flows to minimize contamination and to provide efficient production operations. For all product categories and all process steps, materials, components and products must be segregated for materials incoming, quarantine, release and rejected and outgoing products to be quarantined and released. Design and layout segregation protect the open product from environmental contamination as it progresses through a series of unit operations. The segregation can only be accomplished through physical, environmental and through less effective chronological time separation and procedural. For example, segregation by space (spatial) may include a dedicated built in path of travel and segregation by time may include sequencing clean and dirty items or materials at different stages of cleanliness through the same area. Other segregation by environmental control may include a classified area for a unit operation where the products are exposed and local protection system may be inadequate. Designed segregation by closed systems avoids the additional measures needed to protect an open process. Good CGMP design features include dedicated and adequate wash/storage areas, interior windows for good communications and safety.
FIG. 1 shows a layout of a conventional pharmaceutical manufacturing facility 101. As shown, the facility comprises a rectangular shaped building with two levels 103a and 103b. Typically, the production area 140 is located on the ground level 103a while non-production areas are located on the second level 103b. Also located on the ground level are storage area 195, and packing area 197. Additional areas, such as changing area 194, cafeteria 191, engineering area 193 can also be included on the ground level. The non-production areas on the second level include administration area 108, laboratory area 141, storage area 145, and HVAC plant room 146. In some facilities, all the different areas are provided in a single level.
The various production suites 165 form different stages of a production line for manufacturing pharmaceutical products. Products are tested in their various stages for quality control. The finished products are transferred to the packing area for packaging and then to the storage area.
Although such a layout may comply with CGMP, it is, however, inefficient. For example, quality assurance and quality control cannot be easily carried out in such conventional layouts. The different production stages are not visible from a single point, making it inconvenient to monitor, identify, and verify the manufacturing process. Such deficiencies increase process time in identification and quality monitoring. Therefore, a manufacturer incurs additional costs to ensure that the process can be monitored adequately for verification and quality control, rendering such layouts not cost effective.
From the foregoing discussion, it is desirable to provide a more efficient and cost effective layout for a manufacturing facility.